This grant proposal focuses our sustained laboratory and clinical research experience in animal and human stem cell biology and leukemia to extend exciting new investigations on normal tissue-specific and cancer stem cells. The investigators in this PPG look forward to discovering key information about the defining characteristics of cancer stem cells. This knowledge will enable us to develop new methods to better identify and isolate these rare cells for further study. In addition, this PPG seeks increased understanding of the pathophysiologic mechanisms of cancer stem cells, particularly the signaling pathways that these cells depend on for their persistence and other malignant behavior. This basic information will suggest new clinical cancer stem cell targets, which we will proceed to attack via pharmacologic and biologic approaches. Both within the Projects and in interactions among the Projects and Cores, clinical research and laboratory inquiries will proceed in parallel, so that insights generated in one sphere will translate to, and promote progress in the other. We believe that our highly interactive, closely integrated, translational approach is the best way to determine mechanisms of normal and malignant stem cell biology, and simultaneously to develop new treatments utilizing normal stem cells and targeting malignant stem cells in human diseases. Relevance: There is growing evidence suggesting that many cancers originate in early (stem or progenitor) cells and that the mature cancers continue to be maintained by a stem-progenitor cell hierarchy. Our group has provided important evidence demonstrating the existence of discrete populations of cancer stem cells in human diseases, and our results support the prediction that cancer recurrence in patients after chemotherapy may be due to failure to eradicate the rare, sustaining cancer stem cell population, despite massive reduction of the predominant bulk population of mature cancer cells. The investigators in this PPG look forward to discovering key information about the defining characteristics and molecular mechanisms of cancer stem cells that will provide new ways to identify and attack cancer stem cells therapeutically.